VIP fragments and methods of use

ABSTRACT

The invention relates to composition comprising a pharmaceutically effective amount of one or more functional vasoactive intestinal peptide (VIP) fragments, and the use of those compositions in the treatment of fibrosis, hypertension and other disorders.

TECHNICAL FIELD

This invention relates to compositions and methods for therapeutic orprophylactic treatment of myocardial fibrosis or associated conditions.In particular this invention concerns compositions comprising certainactive fragments of VIP and their use in the treatment of myocardialfibrosis.

BACKGROUND

Any discussion of the prior art throughout the specification should inno way be considered as an admission that such prior art is widely knownor forms part of common general knowledge in the field.

In myocardial fibrosis, heart muscle is replaced by fibrous or scartissue. This can interfere with the flexibility of the heart muscle. Itcan lead to a decrease in function and, eventually, to overt heartfailure. Use of VIP and certain fragments of VIP in therapeutic andprophylactic treatment of myocardial fibrosis and related conditions wasdescribed in PCT/AU2005/000835, incorporated in its entirety herein byreference.

Conventional view of structure/function relationship with respect to VIPactivity is that the N-terminal amino acid residues (1-5) are importantand necessary for signal delivery once VIP binds to its receptor.Further, there are certain key amino acid residues throughout the VIPmolecule, distal to the N-terminus, that are important for receptorbinding. This would suggest that fragments of VIP lacking either theN-terminal residues or significant portions that encompass the receptorbinding residues would not be fully functional. Earlier studies with twoVIP fragments, described in PCT/AU2005/000835, indicate that suchfragments of VIP could be active, at least in the treatment ofmyocardial fibrosis.

It is an object of the present invention to identify additionalfragments of VIP that are active in the treatment of conditions such asmyocardial fibrosis, that would overcome certain disadvantagesassociated with using the entire VIP molecule or large portions thereof,or at least provide a useful alternative.

SUMMARY OF THE INVENTION

Despite the currently prevailing view, it was surprisingly found thatactivity of VIP and its fragments in the treatment and/or prevention ofmyocardial fibrosis is not curtailed by either deletion of theN-terminal residues of VIP or the majority of amino acid residuesresponsible for receptor binding.

In a broad aspect, the invention relates to compositions forprophylactic or therapeutic treatment of myocardial fibrosis or anassociated condition, such as hypertension, comprising apharmaceutically effective amount of one or more functional vasoactiveintestinal peptide (VIP) fragments. Most preferably, the (VIP) fragmentshave as a core sequence amino acid residues 6 to 10 of native VIP (SEQID NO: 1), or conservative substitutions thereof. However, they may alsohave as a core sequence amino acid residues 16 to 25 of native VIP (SEQID NO: 1), or conservative substitutions thereof.

Accordingly, in a first aspect the invention provides a composition forprophylactic or therapeutic treatment of myocardial fibrosis or anassociated condition, the composition comprising a pharmaceuticallyeffective amount of one or more functional vasoactive intestinal peptide(VIP) fragments having as a core sequence amino acid residues 6 to 10 ofnative VIP (SEQ ID NO: 1), or conservative substitutions thereof.

The preferred active fragments of VIP are VIP(4-16) (SEQ ID NO: 35),VIP(6-16) (SEQ ID NO: 72), VIP(6-10) (SEQ ID NO: 66), VIP(6-12) (SEQ IDNO: 68), VIP(6-20) (SEQ ID NO: 76) and VIP(6-24) (SEQ ID NO: 80), withthe proviso that fragments VIP(1-12) (SEQ ID NO: 91) and VIP(6-28) (SEQID NO: 84) are not included. However, the use of VIP fragments,including VIP(1-12) (SEQ ID NO: 91) and VIP(6-28) (SEQ ID NO: 84) forthe treatment of myocardial fibrosis and other associated conditionssuch as hypertension are encompassed by the present invention

The pharmaceutically effective amount of an active VIP fragment willvary according to the patient and/or with the severity of the disease orcondition. These variables can be ascertained by one skilled in the artby routine experimentation. An appropriate dosage range, as a startingpoint, can be derived from dosages administered in the animal modelsdescribed herein, or with reference to PCT/AU2005/000835.

Accordingly, in a second aspect the invention provides a composition forprophylactic or therapeutic treatment of myocardial fibrosis or anassociated condition, the composition comprising a pharmaceuticallyeffective amount of one or more functional vasoactive intestinal peptide(VIP) fragments having as a core sequence amino acid residues 16 to 25of native VIP (SEQ ID NO: 1), or conservative substitutions thereof.

Accordingly, in a third aspect the invention provides a composition forprophylactic or therapeutic treatment of myocardial fibrosis or anassociated condition, the composition comprising a pharmaceuticallyeffective amount of one or more functional vasoactive intestinal peptide(VIP) fragments selected from the group consisting of VIP(4-16) (SEQ IDNO: 35), VIP(6-16) (SEQ ID NO: 72), VIP(6-10) (SEQ ID NO: 66), VIP(6-12)(SEQ ID NO: 68), VIP(10-28) (SEQ ID NO: 92), VIP(16-28), (SEQ ID NO: 88)VIP(6-20) (SEQ ID NO: 76) and VIP(6-24) (SEQ ID NO: 80), or conservativesubstitutions thereof.

Accordingly, in a fourth aspect the invention provides a composition forprophylactic or therapeutic treatment of myocardial fibrosis or anassociated condition, the composition comprising a pharmaceuticallyeffective amount of one or more functional vasoactive intestinal peptide(VIP) fragments selected from the group listed in Table 1, orconservative substitutions thereof.

The compositions of the invention may be administered in conjunctionwith a pharmaceutically acceptable carrier, which may be any of thoseknown in the art or devised hereafter and suitable for the intended use.As well as carriers, the pharmaceutical composition of the invention mayinclude other ingredients, including dyes, preservatives, buffers andanti-oxidants, for example. The compositions of the present inventionmay also include other active agents useful in the treatment ofcardiovascular conditions.

The pharmaceutical composition of the invention may take any suitableform, but is preferably suitable for administration by oral,intravenous, intramuscular or subcuticular routes. Other methods ofadministration such as patches, snuffs, nasal sprays and the like willbe clear to those skilled in the art.

According to a fifth aspect the invention provides a method oftherapeutic treatment of myocardial fibrosis or an associated conditionin a subject, the method including administering to the subject withmyocardial fibrosis or an associated condition, a composition accordingto the invention.

The compositions of the invention may be used to prevent or slow downprogression of established myocardial fibrosis, as well as to reduce thedegree of established fibrosis.

According to a sixth aspect the invention provides a method ofprophylactic treatment of myocardial fibrosis or an associated conditionin a subject, the method including administering to the subject at riskof developing myocardial fibrosis or an associated condition, acomposition according to the invention.

With respect to prophylactic treatment it will be understood that such atreatment would benefit particularly subjects who are at risk ofdeveloping myocardial fibrosis or an associated condition. As an exampleof subjects in the risk category are those having hypertension,diabetes, myocarditis, ischaemic heart disease, drugs such asdaunorubicin and others which are used in cancer chemotherapy, geneticpredisposition, other conditions such as Conn's Syndrome andPhaeochromocytoma, high salt diet and the like. The prophylactictreatment may be used to prevent or slow down the development offibrosis in the at risk group. High proportion of subjects may alreadyhave signs of early heart failure on echocardiography. For example suchsigns are present in nearly 80% of patients with hypertension. Theincidence in diabetics is even higher.

According to a seventh aspect the invention provides a method ofprophylactic or therapeutic treatment of congestive cardiac failure in asubject, the method including administering to the subject at risk ofdeveloping congestive cardiac failure, a pharmaceutical compositionaccording to the invention.

According to a eighth aspect the invention provides a method of reducingthe levels, inhibiting or reducing the production, of pro-fibroticmediators in a subject, the method including administering to thesubject a composition according to the invention.

According to an ninth aspect the invention provides a method of reducingcollagen formation or enhancing collagen degradation in the cardiacmuscle of a subject, the method including administering to the subject acomposition according to the invention.

According to a tenth aspect the invention provides a method oftherapeutic or prophylactic treatment of hypertension, the methodincluding administering to the subject a composition according to theinvention.

According to a eleventh aspect the invention provides a method oflowering blood pressure in a subject, the method including administeringto a subject a a composition according to the invention.

It will be apparent to one skilled in the art that the pattern of use ofthe compositions of the invention may need to be altered for optimumeffect. It may be necessary to take into account the nature of thedisease or condition as well as its severity.

The associated conditions, which may be subject to prevention ortreatment by the compositions of the invention, may include leftventricular hypertrophy, diastolic dysfunction, myocarditis,cardiomyopathy, left ventricular dysfunction and congestive cardiacfailure (for which myocardial fibrosis may be an underlying pathology).The associated condition may also include conditions which give rise togeneration of profibrotic mediators or conditions which predispose asubject to myocardial fibrosis, such as for example hypertension and/orhigh salt intake, diseases such as diabetes and the like.

Further aspect of the invention includes the use of a composition of theinvention in the manufacture of a medicament for the prophylactic ortherapeutic treatment of myocardial fibrosis, or an associatedcondition.

Yet another aspect of the invention provides the use of a composition ofthe invention in the manufacture of a medicament for the prophylactic ortherapeutic treatment of congestive cardiac failure.

In another aspect, the invention relates to a composition comprising apharmaceutically effective amount of one or more functional vasoactiveintestinal peptide (VIP) fragments with the proviso that fragmentsVIP(1-12) (SEQ ID NO: 91) and VIP(6-28) (SEQ ID NO: 84) are notincluded.

In another aspect, the invention relates to a composition comprising apharmaceutically effective amount of one or more functional vasoactiveintestinal peptide (VIP) fragments having as a core sequence amino acidresidues 6-10 or 16-25 of native VIP (SEQ ID NO: 1), or conservativesubstitutions thereof. Preferably, fragments VIP(1-12) (SEQ ID NO: 91)and VIP(6-28) (SEQ ID NO: 84) are not included.

Preferably, the VIP fragment is one or more fragments selected from thegroup consisting of: VIP(4-10) (SEQ ID NO: 29), VIP(4-11) (SEQ ID NO:30), VIP(4-12) (SEQ ID NO: 31), VIP(4-13) (SEQ ID NO: 328), VIP(4-14)(SEQ ID NO: 33), VIP(4-15) (SEQ ID NO: 34), VIP(4-16) (SEQ ID NO: 35),VIP(4-17) (SEQ ID NO: 36), VIP(4-18) (SEQ ID NO: 37), VIP(4-19) (SEQ IDNO: 38), VIP(4-20) (SEQ ID NO: 39), VIP(4-21) (SEQ ID NO: 40), VIP(4-22)(SEQ ID NO: 41), VIP(4-23) (SEQ ID NO: 42), VIP(4-24) (SEQ ID NO: 43),VIP(4-25) (SEQ ID NO: 44), VIP(4-26) (SEQ ID NO: 45), VIP(4-27) (SEQ IDNO: 46), VIP(4-28) (SEQ ID NO: 90), VIP(5-10) (SEQ ID NO: 47), VIP(5-11)(SEQ ID NO: 48), VIP(5-12) (SEQ ID NO: 49), VIP(5-13) (SEQ ID NO: 50),VIP(5-14) (SEQ ID NO: 51), VIP(5-15) (SEQ ID NO: 52), VIP(5-16) (SEQ IDNO: 53), VIP(5-17) (SEQ ID NO: 54), VIP(5-18) (SEQ ID NO: 55), VIP(5-19)(SEQ ID NO: 56), VIP(5-20) (SEQ ID NO: 57), VIP(5-21) (SEQ ID NO: 58),VIP(5-22) (SEQ ID NO: 59), VIP(5-23) (SEQ ID NO: 60), VIP(5-24) (SEQ IDNO: 61), VIP(5-25) (SEQ ID NO: 62), VIP(5-26) (SEQ ID NO: 63), VIP(5-27)(SEQ ID NO: 64), VIP(5-28) (SEQ ID NO: 65), VIP(6-10) (SEQ ID NO: 66),VIP(6-11) (SEQ ID NO: 67), VIP(6-12) (SEQ ID NO: 68), VIP(6-13) (SEQ IDNO: 69), VIP(6-14) (SEQ ID NO: 70), VIP(6-15) (SEQ ID NO: 71), VIP(6-16)(SEQ ID NO: 72), VIP(6-17) (SEQ ID NO: 73), VIP(6-18) (SEQ ID NO: 74),VIP(6-19) (SEQ ID NO: 75), VIP(6-20) (SEQ ID NO: 76), VIP(6-21) (SEQ IDNO: 77), VIP(6-22) (SEQ ID NO: 78), VIP(6-23) (SEQ ID NO: 79), VIP(6-24)(SEQ ID NO: 80), VIP(6-25) (SEQ ID NO: 81), VIP(6-26) (SEQ ID NO: 82),VIP(6-27) (SEQ ID NO: 83), VIP(10-28) (SEQ ID NO: 92), VIP(16-25) (SEQID NO: 85), VIP(16-26) (SEQ ID NO: 86), VIP(16-27) (SEQ ID NO: 87),VIP(16-28) (SEQ ID NO: 88) or conservative substitutions thereof.

In another aspect, the invention relates to a composition forprophylactic or therapeutic treatment of myocardial fibrosis or anassociated condition, the composition comprising a pharmaceuticallyeffective amount of one or more functional vasoactive intestinal peptide(VIP) fragments wherein the VIP fragment is one or more fragmentsselected from the group consisting of: VIP(4-10) (SEQ ID NO: 29),VIP(4-11) (SEQ ID NO: 30), VIP(4-12) (SEQ ID NO: 31), VIP(4-13) (SEQ IDNO: 328), VIP(4-14) (SEQ ID NO: 33), VIP(4-15) (SEQ ID NO: 34),VIP(4-16) (SEQ ID NO: 35), VIP(4-17) (SEQ ID NO: 36), VIP(4-18) (SEQ IDNO: 37), VIP(4-19) (SEQ ID NO: 38), VIP(4-20) (SEQ ID NO: 39), VIP(4-21)(SEQ ID NO: 40), VIP(4-22) (SEQ ID NO: 41), VIP(4-23) (SEQ ID NO: 42),VIP(4-24) (SEQ ID NO: 43), VIP(4-25) (SEQ ID NO: 44), VIP(4-26) (SEQ IDNO: 45), VIP(4-27) (SEQ ID NO: 46), VIP(4-28) (SEQ ID NO: 90), VIP(5-10)(SEQ ID NO: 47), VIP(5-11) (SEQ ID NO: 48), VIP(5-12) (SEQ ID NO: 49),VIP(5-13) (SEQ ID NO: 50), VIP(5-14) (SEQ ID NO: 51), VIP(5-15) (SEQ IDNO: 52), VIP(5-16) (SEQ ID NO: 53), VIP(5-17) (SEQ ID NO: 54), VIP(5-18)(SEQ ID NO: 55), VIP(5-19) (SEQ ID NO: 56), VIP(5-20) (SEQ ID NO: 57),VIP(5-21) (SEQ ID NO: 58), VIP(5-22) (SEQ ID NO: 59), VIP(5-23) (SEQ IDNO: 60), VIP(5-24) (SEQ ID NO: 61), VIP(5-25) (SEQ ID NO: 62), VIP(5-26)(SEQ ID NO: 63), VIP(5-27) (SEQ ID NO: 64), VIP(5-28) (SEQ ID NO: 65),VIP(6-10) (SEQ ID NO: 66), VIP(6-11) (SEQ ID NO: 67), VIP(6-12) (SEQ IDNO: 68), VIP(6-13) (SEQ ID NO: 69), VIP(6-14) (SEQ ID NO: 70), VIP(6-15)(SEQ ID NO: 71), VIP(6-16) (SEQ ID NO: 72), VIP(6-17) (SEQ ID NO: 73),VIP(6-18) (SEQ ID NO: 74), VIP(6-19) (SEQ ID NO: 75), VIP(6-20) (SEQ IDNO: 76), VIP(6-21) (SEQ ID NO: 77), VIP(6-22) (SEQ ID NO: 78), VIP(6-23)(SEQ ID NO: 79), VIP(6-24) (SEQ ID NO: 80), VIP(6-25) (SEQ ID NO: 81),VIP(6-26) (SEQ ID NO: 82), VIP(6-27) (SEQ ID NO: 83), VIP(10-28) (SEQ IDNO: 92), VIP(16-25) (SEQ ID NO: 85), VIP(16-26) (SEQ ID NO: 86),VIP(16-27) (SEQ ID NO: 87), VIP(16-28) (SEQ ID NO: 88) or conservativesubstitutions thereof.

In another aspect, the invention relates to a composition forprophylactic or therapeutic treatment of hypertension, the compositioncomprising a pharmaceutically effective amount of one or more functionalvasoactive intestinal peptide (VIP) fragments wherein the VIP fragmentis one or more fragments selected from the group consisting of:VIP(4-10) (SEQ ID NO: 29), VIP(4-11) (SEQ ID NO: 30), VIP(4-12) (SEQ IDNO: 31), VIP(4-13) (SEQ ID NO: 328), VIP(4-14) (SEQ ID NO: 33),VIP(4-15) (SEQ ID NO: 34), VIP(4-16) (SEQ ID NO: 35), VIP(4-17) (SEQ IDNO: 36), VIP(4-18) (SEQ ID NO: 37), VIP(4-19) (SEQ ID NO: 38), VIP(4-20)(SEQ ID NO: 39), VIP(4-21) (SEQ ID NO: 40), VIP(4-22) (SEQ ID NO: 41),VIP(4-23) (SEQ ID NO: 42), VIP(4-24) (SEQ ID NO: 43), VIP(4-25) (SEQ IDNO: 44), VIP(4-26) (SEQ ID NO: 45), VIP(4-27) (SEQ ID NO: 46), VIP(4-28)(SEQ ID NO: 90), VIP(5-10) (SEQ ID NO: 47), VIP(5-11) (SEQ ID NO: 48),VIP(5-12) (SEQ ID NO: 49), VIP(5-13) (SEQ ID NO: 50), VIP(5-14) (SEQ IDNO: 51), VIP(5-15) (SEQ ID NO: 52), VIP(5-16) (SEQ ID NO: 53), VIP(5-17)(SEQ ID NO: 54), VIP(5-18) (SEQ ID NO: 55), VIP(5-19) (SEQ ID NO: 56),VIP(5-20) (SEQ ID NO: 57), VIP(5-21) (SEQ ID NO: 58), VIP(5-22) (SEQ IDNO: 59), VIP(5-23) (SEQ ID NO: 60), VIP(5-24) (SEQ ID NO: 61), VIP(5-25)(SEQ ID NO: 62), VIP(5-26) (SEQ ID NO: 63), VIP(5-27) (SEQ ID NO: 64),VIP(5-28) (SEQ ID NO: 65), VIP(6-10) (SEQ ID NO: 66), VIP(6-11) (SEQ IDNO: 67), VIP(6-12) (SEQ ID NO: 68), VIP(6-13) (SEQ ID NO: 69), VIP(6-14)(SEQ ID NO: 70), VIP(6-15) (SEQ ID NO: 71), VIP(6-16) (SEQ ID NO: 72),VIP(6-17) (SEQ ID NO: 73), VIP(6-18) (SEQ ID NO: 74), VIP(6-19) (SEQ IDNO: 75), VIP(6-20) (SEQ ID NO: 76), VIP(6-21) (SEQ ID NO: 77), VIP(6-22)(SEQ ID NO: 78), VIP(6-23) (SEQ ID NO: 79), VIP(6-24) (SEQ ID NO: 80),VIP(6-25) (SEQ ID NO: 81), VIP(6-26) (SEQ ID NO: 82), VIP(6-27) (SEQ IDNO: 83), VIP(10-28) (SEQ ID NO: 92), VIP(16-25) (SEQ ID NO: 85),VIP(16-26) (SEQ ID NO: 86), VIP(16-27) (SEQ ID NO: 87), VIP(16-28) (SEQID NO: 88) or conservative substitutions thereof.

Preferably, compositions according to the present invention areadministered in conjunction with a pharmaceutically acceptable carrier.They may preferably be administered in conjunction with one or moreother active agents useful in the treatment of cardiovascularconditions. They may, for preference, be formulated for administrationby oral, intravenous, intramuscular or subcuticular routes.

In another aspect, the invention relates to method of therapeutic orprophylactic treatment of myocardial fibrosis or an associated conditionin a subject, the method including administering to a subject acomposition including a pharmaceutically effective amount of one or morefunctional vasoactive intestinal peptide (VIP) fragments having as acore sequence amino acid residues 6-10 or 16-25 of native VIP (SEQ IDNO: 1), or conservative substitutions thereof.

In another aspect, the invention relates to a method of therapeutic orprophylactic treatment of myocardial fibrosis or an associated conditionin a subject, the method including administering to a subject acomposition according to the present invention.

In another aspect, the invention relates to a method of therapeutic orprophylactic treatment of myocardial fibrosis or an associated conditionin a subject, the method including administering to a subject acomposition including one or more VIP fragments selected from the groupconsisting of VIP(4-10) (SEQ ID NO: 29), VIP(4-11) (SEQ ID NO: 30),VIP(4-12) (SEQ ID NO: 31), VIP(4-13) (SEQ ID NO: 328), VIP(4-14) (SEQ IDNO: 33), VIP(4-15) (SEQ ID NO: 34), VIP(4-16) (SEQ ID NO: 35), VIP(4-17)(SEQ ID NO: 36), VIP(4-18) (SEQ ID NO: 37), VIP(4-19) (SEQ ID NO: 38),VIP(4-20) (SEQ ID NO: 39), VIP(4-21) (SEQ ID NO: 40), VIP(4-22) (SEQ IDNO: 41), VIP(4-23) (SEQ ID NO: 42), VIP(4-24) (SEQ ID NO: 43), VIP(4-25)(SEQ ID NO: 44), VIP(4-26) (SEQ ID NO: 45), VIP(4-27) (SEQ ID NO: 46),VIP(4-28) (SEQ ID NO: 90), VIP(5-10) (SEQ ID NO: 47), VIP(5-11) (SEQ IDNO: 48), VIP(5-12) (SEQ ID NO: 49), VIP(5-13) (SEQ ID NO: 50), VIP(5-14)(SEQ ID NO: 51), VIP(5-15) (SEQ ID NO: 52), VIP(5-16) (SEQ ID NO: 53),VIP(5-17) (SEQ ID NO: 54), VIP(5-18) (SEQ ID NO: 55), VIP(5-19) (SEQ IDNO: 56), VIP(5-20) (SEQ ID NO: 57), VIP(5-21) (SEQ ID NO: 58), VIP(5-22)(SEQ ID NO: 59), VIP(5-23) (SEQ ID NO: 60), VIP(5-24) (SEQ ID NO: 61),VIP(5-25) (SEQ ID NO: 62), VIP(5-26) (SEQ ID NO: 63), VIP(5-27) (SEQ IDNO: 64), VIP(5-28) (SEQ ID NO: 65), VIP(6-10) (SEQ ID NO: 66), VIP(6-11)(SEQ ID NO: 67), VIP(6-12) (SEQ ID NO: 68), VIP(6-13) (SEQ ID NO: 69),VIP(6-14) (SEQ ID NO: 70), VIP(6-15) (SEQ ID NO: 71), VIP(6-16) (SEQ IDNO: 72), VIP(6-17) (SEQ ID NO: 73), VIP(6-18) (SEQ ID NO: 74), VIP(6-19)(SEQ ID NO: 75), VIP(6-20) (SEQ ID NO: 76), VIP(6-21) (SEQ ID NO: 77),VIP(6-22) (SEQ ID NO: 78), VIP(6-23) (SEQ ID NO: 79), VIP(6-24) (SEQ IDNO: 80), VIP(6-25) (SEQ ID NO: 81), VIP(6-26) (SEQ ID NO: 82), VIP(6-27)(SEQ ID NO: 83), VIP(10-28) (SEQ ID NO: 92), VIP(16-25) (SEQ ID NO: 85),VIP(16-26) (SEQ ID NO: 86), VIP(16-27) (SEQ ID NO: 87), VIP(16-28) (SEQID NO: 88) or conservative substitutions thereof.

Preferably, the method is used to prevent or slow down progression ofestablished myocardial fibrosis, or alternatively, to reduce the degreeof established fibrosis.

Preferably the associated condition is hypertension, diabetes,myocarditis, ischaemic heart disease, left ventricular hypertrophy,diastolic dysfunction, myocarditis, cardiomyopathy, left ventriculardysfunction, congestive cardiac failure (for which myocardial fibrosismay be an underlying pathology), treatment with drugs such asdaunorubicin and others which are used in cancer chemotherapy, geneticpredisposition, other conditions such as Conn's Syndrome andPhaeochromocytoma, high salt diet and the like.

Preferably the associated condition includes conditions which give riseto generation of profibrotic mediators or conditions which predispose asubject to myocardial fibrosis.

Preferably the prophylactic treatment is used to prevent or slow downthe development of fibrosis in the at risk group.

Preferably the condition is hypertension and/or high salt intake,diseases such as diabetes and the like. Most preferably, the conditionis hypertension.

In another aspect, the invention relates to method of therapeutic orprophylactic treatment of myocardial fibrosis by reducing hypertension,the method including administering to a subject in need or at risk acomposition including a VIP fragment.

In another aspect, the invention relates to a method of therapeutic orprophylactic treatment of myocardial fibrosis by reducing hypertension,the method including administering an associated condition a compositionincluding one or more VIP fragments selected from the group consistingof VIP(4-10) (SEQ ID NO: 29), VIP(4-11) (SEQ ID NO: 30), VIP(4-12) (SEQID NO: 31), VIP(4-13) (SEQ ID NO: 328), VIP(4-14) (SEQ ID NO: 33),VIP(4-15) (SEQ ID NO: 34), VIP(4-16) (SEQ ID NO: 35), VIP(4-17) (SEQ IDNO: 36), VIP(4-18) (SEQ ID NO: 37), VIP(4-19) (SEQ ID NO: 38), VIP(4-20)(SEQ ID NO: 39), VIP(4-21) (SEQ ID NO: 40), VIP(4-22) (SEQ ID NO: 41),VIP(4-23) (SEQ ID NO: 42), VIP(4-24) (SEQ ID NO: 43), VIP(4-25) (SEQ IDNO: 44), VIP(4-26) (SEQ ID NO: 45), VIP(4-27) (SEQ ID NO: 46), VIP(4-28)(SEQ ID NO: 90), VIP(5-10) (SEQ ID NO: 47), VIP(5-11) (SEQ ID NO: 48),VIP(5-12) (SEQ ID NO: 49), VIP(5-13) (SEQ ID NO: 50), VIP(5-14) (SEQ IDNO: 51), VIP(5-15) (SEQ ID NO: 52), VIP(5-16) (SEQ ID NO: 53), VIP(5-17)(SEQ ID NO: 54), VIP(5-18) (SEQ ID NO: 55), VIP(5-19) (SEQ ID NO: 56),VIP(5-20) (SEQ ID NO: 57), VIP(5-21) (SEQ ID NO: 58), VIP(5-22) (SEQ IDNO: 59), VIP(5-23) (SEQ ID NO: 60), VIP(5-24) (SEQ ID NO: 61), VIP(5-25)(SEQ ID NO: 62), VIP(5-26) (SEQ ID NO: 63), VIP(5-27) (SEQ ID NO: 64),VIP(5-28) (SEQ ID NO: 65), VIP(6-10) (SEQ ID NO: 66), VIP(6-11) (SEQ IDNO: 67), VIP(6-12) (SEQ ID NO: 68), VIP(6-13) (SEQ ID NO: 69), VIP(6-14)(SEQ ID NO: 70), VIP(6-15) (SEQ ID NO: 71), VIP(6-16) (SEQ ID NO: 72),VIP(6-17) (SEQ ID NO: 73), VIP(6-18) (SEQ ID NO: 74), VIP(6-19) (SEQ IDNO: 75), VIP(6-20) (SEQ ID NO: 76), VIP(6-21) (SEQ ID NO: 77), VIP(6-22)(SEQ ID NO: 78), VIP(6-23) (SEQ ID NO: 79), VIP(6-24) (SEQ ID NO: 80),VIP(6-25) (SEQ ID NO: 81), VIP(6-26) (SEQ ID NO: 82), VIP(6-27) (SEQ IDNO: 83), VIP(10-28) (SEQ ID NO: 92), VIP(16-25) (SEQ ID NO: 85),VIP(16-26) (SEQ ID NO: 86), VIP(16-27) (SEQ ID NO: 87), VIP(16-28) (SEQID NO: 88) or conservative substitutions thereof.

Preferably, the method is used to prevent or slow down progression ofestablished myocardial fibrosis.

Preferably the method is used to reduce the degree of establishedfibrosis.

In another aspect, the invention relates to method of lowering bloodpressure comprising administering to a subject in need thereof acomposition including a pharmaceutically effective amount of one or moreof vasoactive intestinal peptide (VIP) and/or active fragment thereofwith a pharmaceutically acceptable carrier.

In another aspect, the invention relates to a method of lowering bloodpressure comprising administering to a subject in need thereof acomposition including a pharmaceutically effective amount of one or morefunctional vasoactive intestinal peptide (VIP) fragments having as acore sequence amino acid residues 6-10 or 16-25 of native VIP (SEQ IDNO: 1), or conservative substitutions thereof.

In another aspect, the invention relates to a method of lowering bloodpressure, the method including administering to a subject a compositionincluding one or more VIP fragments selected from the group consistingof VIP(4-10) (SEQ ID NO: 29), VIP(4-11) (SEQ ID NO: 30), VIP(4-12) (SEQID NO: 31), VIP(4-13) (SEQ ID NO: 328), VIP(4-14) (SEQ ID NO: 33),VIP(4-15) (SEQ ID NO: 34), VIP(4-16) (SEQ ID NO: 35), VIP(4-17) (SEQ IDNO: 36), VIP(4-18) (SEQ ID NO: 37), VIP(4-19) (SEQ ID NO: 38), VIP(4-20)(SEQ ID NO: 39), VIP(4-21) (SEQ ID NO: 40), VIP(4-22) (SEQ ID NO: 41),VIP(4-23) (SEQ ID NO: 42), VIP(4-24) (SEQ ID NO: 43), VIP(4-25) (SEQ IDNO: 44), VIP(4-26) (SEQ ID NO: 45), VIP(4-27) (SEQ ID NO: 46), VIP(4-28)(SEQ ID NO: 90), VIP(5-10) (SEQ ID NO: 47), VIP(5-11) (SEQ ID NO: 48),VIP(5-12) (SEQ ID NO: 49), VIP(5-13) (SEQ ID NO: 50), VIP(5-14) (SEQ IDNO: 51), VIP(5-15) (SEQ ID NO: 52), VIP(5-16) (SEQ ID NO: 53), VIP(5-17)(SEQ ID NO: 54), VIP(5-18) (SEQ ID NO: 55), VIP(5-19) (SEQ ID NO: 56),VIP(5-20) (SEQ ID NO: 57), VIP(5-21) (SEQ ID NO: 58), VIP(5-22) (SEQ IDNO: 59), VIP(5-23) (SEQ ID NO: 60), VIP(5-24) (SEQ ID NO: 61), VIP(5-25)(SEQ ID NO: 62), VIP(5-26) (SEQ ID NO: 63), VIP(5-27) (SEQ ID NO: 64),VIP(5-28) (SEQ ID NO: 65), VIP(6-10) (SEQ ID NO: 66), VIP(6-11) (SEQ IDNO: 67), VIP(6-12) (SEQ ID NO: 68), VIP(6-13) (SEQ ID NO: 69), VIP(6-14)(SEQ ID NO: 70), VIP(6-15) (SEQ ID NO: 71), VIP(6-16) (SEQ ID NO: 72),VIP(6-17) (SEQ ID NO: 73), VIP(6-18) (SEQ ID NO: 74), VIP(6-19) (SEQ IDNO: 75), VIP(6-20) (SEQ ID NO: 76), VIP(6-21) (SEQ ID NO: 77), VIP(6-22)(SEQ ID NO: 78), VIP(6-23) (SEQ ID NO: 79), VIP(6-24) (SEQ ID NO: 80),VIP(6-25) (SEQ ID NO: 81), VIP(6-26) (SEQ ID NO: 82), VIP(6-27) (SEQ IDNO: 83), VIP(10-28) (SEQ ID NO: 92), VIP(16-25) (SEQ ID NO: 85),VIP(16-26) (SEQ ID NO: 86), VIP(16-27) (SEQ ID NO: 87), VIP(16-28) (SEQID NO: 88) or conservative substitutions thereof.

In another aspect, the invention relates to a method of treatinghypertension comprising administering to a subject in need thereof acomposition including a pharmaceutically effective amount of one or morefunctional vasoactive intestinal peptide (VIP) fragments having as acore sequence amino acid residues 6-10 or 16-25 of native VIP (SEQ IDNO: 1), or conservative substitutions thereof.

In another aspect, the invention relates to a method of treatinghypertension comprising administering to a subject in need thereof acomposition including a pharmaceutically effective amount of one or morefunctional vasoactive intestinal peptide (VIP) fragments having as acore sequence amino acid residues 6-10 or 16-25 of native VIP (SEQ IDNO: 1), or conservative substitutions thereof.

In another aspect, the invention relates to a method of therapeutic orprophylactic treatment of hypertension, the method includingadministering to a subject a composition including one or more VIPfragments selected from the group consisting of VIP(4-10) (SEQ ID NO:29), VIP(4-11) (SEQ ID NO: 30), VIP(4-12) (SEQ ID NO: 31), VIP(4-13)(SEQ ID NO: 328), VIP(4-14) (SEQ ID NO: 33), VIP(4-15) (SEQ ID NO: 34),VIP(4-16) (SEQ ID NO: 35), VIP(4-17) (SEQ ID NO: 36), VIP(4-18) (SEQ IDNO: 37), VIP(4-19) (SEQ ID NO: 38), VIP(4-20) (SEQ ID NO: 39), VIP(4-21)(SEQ ID NO: 40), VIP(4-22) (SEQ ID NO: 41), VIP(4-23) (SEQ ID NO: 42),VIP(4-24) (SEQ ID NO: 43), VIP(4-25) (SEQ ID NO: 44), VIP(4-26) (SEQ IDNO: 45), VIP(4-27) (SEQ ID NO: 46), VIP(4-28) (SEQ ID NO: 90), VIP(5-10)(SEQ ID NO: 47), VIP(5-11) (SEQ ID NO: 48), VIP(5-12) (SEQ ID NO: 49),VIP(5-13) (SEQ ID NO: 50), VIP(5-14) (SEQ ID NO: 51), VIP(5-15) (SEQ IDNO: 52), VIP(5-16) (SEQ ID NO: 53), VIP(5-17) (SEQ ID NO: 54), VIP(5-18)(SEQ ID NO: 55), VIP(5-19) (SEQ ID NO: 56), VIP(5-20) (SEQ ID NO: 57),VIP(5-21) (SEQ ID NO: 58), VIP(5-22) (SEQ ID NO: 59), VIP(5-23) (SEQ IDNO: 60), VIP(5-24) (SEQ ID NO: 61), VIP(5-25) (SEQ ID NO: 62), VIP(5-26)(SEQ ID NO: 63), VIP(5-27) (SEQ ID NO: 64), VIP(5-28) (SEQ ID NO: 65),VIP(6-10) (SEQ ID NO: 66), VIP(6-11) (SEQ ID NO: 67), VIP(6-12) (SEQ IDNO: 68), VIP(6-13) (SEQ ID NO: 69), VIP(6-14) (SEQ ID NO: 70), VIP(6-15)(SEQ ID NO: 71), VIP(6-16) (SEQ ID NO: 72), VIP(6-17) (SEQ ID NO: 73),VIP(6-18) (SEQ ID NO: 74), VIP(6-19) (SEQ ID NO: 75), VIP(6-20) (SEQ IDNO: 76), VIP(6-21) (SEQ ID NO: 77), VIP(6-22) (SEQ ID NO: 78), VIP(6-23)(SEQ ID NO: 79), VIP(6-24) (SEQ ID NO: 80), VIP(6-25) (SEQ ID NO: 81),VIP(6-26) (SEQ ID NO: 82), VIP(6-27) (SEQ ID NO: 83), VIP(10-28) (SEQ IDNO: 92), VIP(16-25) (SEQ ID NO: 85), VIP(16-26) (SEQ ID NO: 86),VIP(16-27) (SEQ ID NO: 87), VIP(16-28) (SEQ ID NO: 88) or conservativesubstitutions thereof.

Preferably, the subject has myocardial fibrosis or an associatedcondition.

In another aspect, the invention relates to a method of reducing thelevels, inhibiting or reducing the production of pro-fibrotic mediatorsin a subject, the method including administering to the subject acomposition according to the present invention.

In another aspect, the invention relates to a method of reducingcollagen formation or enhancing collagen degradation in the cardiacmuscle of a subject, the method including administering to the subject acomposition according to the invention

In another aspect, the invention relates to the use of a compositionaccording to the invention for the manufacture of a medicament for thetreatment or prophylaxis of myocardial fibrosis or an associatedcondition

Preferably, the use is to prevent or slow down progression ofestablished myocardial fibrosis. Alternatively, the use is to prevent orslow down the development of fibrosis in an at risk group. Alsopreferably, the use is to reduce the degree of established fibrosis.

Preferably, the associated condition is hypertension, diabetes,myocarditis, ischaemic heart disease, left ventricular hypertrophy,diastolic dysfunction, myocarditis, cardiomyopathy, left ventriculardysfunction, congestive cardiac failure (for which myocardial fibrosismay be an underlying pathology), treatment with drugs such asdaunorubicin and others which are used in cancer chemotherapy, geneticpredisposition, other conditions such as Conn's Syndrome andPhaeochromocytoma, high salt diet and the like.

Preferably, the associated condition includes conditions which give riseto generation of profibrotic mediators or conditions which predispose asubject to myocardial fibrosis. Preferably, the condition ishypertension and/or high salt intake, diseases such as diabetes and thelike.

In another aspect, the invention relates to the use of a compositionincluding one or more VIP fragments selected from the group consistingof VIP(4-10) (SEQ ID NO: 29), VIP(4-11) (SEQ ID NO: 30), VIP(4-12) (SEQID NO: 31), VIP(4-13) (SEQ ID NO: 328), VIP(4-14) (SEQ ID NO: 33),VIP(4-15) (SEQ ID NO: 34), VIP(4-16) (SEQ ID NO: 35), VIP(4-17) (SEQ IDNO: 36), VIP(4-18) (SEQ ID NO: 37), VIP(4-19) (SEQ ID NO: 38), VIP(4-20)(SEQ ID NO: 39), VIP(4-21) (SEQ ID NO: 40), VIP(4-22) (SEQ ID NO: 41),VIP(4-23) (SEQ ID NO: 42), VIP(4-24) (SEQ ID NO: 43), VIP(4-25) (SEQ IDNO: 44), VIP(4-26) (SEQ ID NO: 45), VIP(4-27) (SEQ ID NO: 46), VIP(4-28)(SEQ ID NO: 90), VIP(5-10) (SEQ ID NO: 47), VIP(5-11) (SEQ ID NO: 48),VIP(5-12) (SEQ ID NO: 49), VIP(5-13) (SEQ ID NO: 50), VIP(5-14) (SEQ IDNO: 51), VIP(5-15) (SEQ ID NO: 52), VIP(5-16) (SEQ ID NO: 53), VIP(5-17)(SEQ ID NO: 54), VIP(5-18) (SEQ ID NO: 55), VIP(5-19) (SEQ ID NO: 56),VIP(5-20) (SEQ ID NO: 57), VIP(5-21) (SEQ ID NO: 58), VIP(5-22) (SEQ IDNO: 59), VIP(5-23) (SEQ ID NO: 60), VIP(5-24) (SEQ ID NO: 61), VIP(5-25)(SEQ ID NO: 62), VIP(5-26) (SEQ ID NO: 63), VIP(5-27) (SEQ ID NO: 64),VIP(5-28) (SEQ ID NO: 65), VIP(6-10) (SEQ ID NO: 66), VIP(6-11) (SEQ IDNO: 67), VIP(6-12) (SEQ ID NO: 68), VIP(6-13) (SEQ ID NO: 69), VIP(6-14)(SEQ ID NO: 70), VIP(6-15) (SEQ ID NO: 71), VIP(6-16) (SEQ ID NO: 72),VIP(6-17) (SEQ ID NO: 73), VIP(6-18) (SEQ ID NO: 74), VIP(6-19) (SEQ IDNO: 75), VIP(6-20) (SEQ ID NO: 76), VIP(6-21) (SEQ ID NO: 77), VIP(6-22)(SEQ ID NO: 78), VIP(6-23) (SEQ ID NO: 79), VIP(6-24) (SEQ ID NO: 80),VIP(6-25) (SEQ ID NO: 81), VIP(6-26) (SEQ ID NO: 82), VIP(6-27) (SEQ IDNO: 83), VIP(10-28) (SEQ ID NO: 92), VIP(16-25) (SEQ ID NO: 85),VIP(16-26) (SEQ ID NO: 86), VIP(16-27) (SEQ ID NO: 87), VIP(16-28) (SEQID NO: 88) or conservative substitutions thereof in the manufacture of amedicament for the therapeutic or prophylactic treatment of myocardialfibrosis or an associated condition.

In another aspect, the invention relates to the use of a compositionincluding one or more VIP fragments selected from the group consistingof VIP(4-10) (SEQ ID NO: 29), VIP(4-11) (SEQ ID NO: 30), VIP(4-12) (SEQID NO: 31), VIP(4-13) (SEQ ID NO: 328), VIP(4-14) (SEQ ID NO: 33),VIP(4-15) (SEQ ID NO: 34), VIP(4-16) (SEQ ID NO: 35), VIP(4-17) (SEQ IDNO: 36), VIP(4-18) (SEQ ID NO: 37), VIP(4-19) (SEQ ID NO: 38), VIP(4-20)(SEQ ID NO: 39), VIP(4-21) (SEQ ID NO: 40), VIP(4-22) (SEQ ID NO: 41),VIP(4-23) (SEQ ID NO: 42), VIP(4-24) (SEQ ID NO: 43), VIP(4-25) (SEQ IDNO: 44), VIP(4-26) (SEQ ID NO: 45), VIP(4-27) (SEQ ID NO: 46), VIP(4-28)(SEQ ID NO: 90), VIP(5-10) (SEQ ID NO: 47), VIP(5-11) (SEQ ID NO: 48),VIP(5-12) (SEQ ID NO: 49), VIP(5-13) (SEQ ID NO: 50), VIP(5-14) (SEQ IDNO: 51), VIP(5-15) (SEQ ID NO: 52), VIP(5-16) (SEQ ID NO: 53), VIP(5-17)(SEQ ID NO: 54), VIP(5-18) (SEQ ID NO: 55), VIP(5-19) (SEQ ID NO: 56),VIP(5-20) (SEQ ID NO: 57), VIP(5-21) (SEQ ID NO: 58), VIP(5-22) (SEQ IDNO: 59), VIP(5-23) (SEQ ID NO: 60), VIP(5-24) (SEQ ID NO: 61), VIP(5-25)(SEQ ID NO: 62), VIP(5-26) (SEQ ID NO: 63), VIP(5-27) (SEQ ID NO: 64),VIP(5-28) (SEQ ID NO: 65), VIP(6-10) (SEQ ID NO: 66), VIP(6-11) (SEQ IDNO: 67), VIP(6-12) (SEQ ID NO: 68), VIP(6-13) (SEQ ID NO: 69), VIP(6-14)(SEQ ID NO: 70), VIP(6-15) (SEQ ID NO: 71), VIP(6-16) (SEQ ID NO: 72),VIP(6-17) (SEQ ID NO: 73), VIP(6-18) (SEQ ID NO: 74), VIP(6-19) (SEQ IDNO: 75), VIP(6-20) (SEQ ID NO: 76), VIP(6-21) (SEQ ID NO: 77), VIP(6-22)(SEQ ID NO: 78), VIP(6-23) (SEQ ID NO: 79), VIP(6-24) (SEQ ID NO: 80),VIP(6-25) (SEQ ID NO: 81), VIP(6-26) (SEQ ID NO: 82), VIP(6-27) (SEQ IDNO: 83), VIP(10-28) (SEQ ID NO: 92), VIP(16-25) (SEQ ID NO: 85),VIP(16-26) (SEQ ID NO: 86), VIP(16-27) (SEQ ID NO: 87), VIP(16-28) (SEQID NO: 88) or conservative substitutions thereof in the manufacture of amedicament for the therapeutic or prophylactic treatment of myocardialfibrosis by reducing hypertension.

In another aspect, the invention relates to the use of VIP or a fragmentthereof in the manufacture of a medicament for lowering blood pressurein a subject. Preferably, the VIP fragment is one or more VIP fragmentsselected from the group consisting of VIP(4-10) (SEQ ID NO: 29),VIP(4-11) (SEQ ID NO: 30), VIP(4-12) (SEQ ID NO: 31), VIP(4-13) (SEQ IDNO: 328), VIP(4-14) (SEQ ID NO: 33), VIP(4-15) (SEQ ID NO: 34),VIP(4-16) (SEQ ID NO: 35), VIP(4-17) (SEQ ID NO: 36), VIP(4-18) (SEQ IDNO: 37), VIP(4-19) (SEQ ID NO: 38), VIP(4-20) (SEQ ID NO: 39), VIP(4-21)(SEQ ID NO: 40), VIP(4-22) (SEQ ID NO: 41), VIP(4-23) (SEQ ID NO: 42),VIP(4-24) (SEQ ID NO: 43), VIP(4-25) (SEQ ID NO: 44), VIP(4-26) (SEQ IDNO: 45), VIP(4-27) (SEQ ID NO: 46), VIP(4-28) (SEQ ID NO: 90), VIP(5-10)(SEQ ID NO: 47), VIP(5-11) (SEQ ID NO: 48), VIP(5-12) (SEQ ID NO: 49),VIP(5-13) (SEQ ID NO: 50), VIP(5-14) (SEQ ID NO: 51), VIP(5-15) (SEQ IDNO: 52), VIP(5-16) (SEQ ID NO: 53), VIP(5-17) (SEQ ID NO: 54), VIP(5-18)(SEQ ID NO: 55), VIP(5-19) (SEQ ID NO: 56), VIP(5-20) (SEQ ID NO: 57),VIP(5-21) (SEQ ID NO: 58), VIP(5-22) (SEQ ID NO: 59), VIP(5-23) (SEQ IDNO: 60), VIP(5-24) (SEQ ID NO: 61), VIP(5-25) (SEQ ID NO: 62), VIP(5-26)(SEQ ID NO: 63), VIP(5-27) (SEQ ID NO: 64), VIP(5-28) (SEQ ID NO: 65),VIP(6-10) (SEQ ID NO: 66), VIP(6-11) (SEQ ID NO: 67), VIP(6-12) (SEQ IDNO: 68), VIP(6-13) (SEQ ID NO: 69), VIP(6-14) (SEQ ID NO: 70), VIP(6-15)(SEQ ID NO: 71), VIP(6-16) (SEQ ID NO: 72), VIP(6-17) (SEQ ID NO: 73),VIP(6-18) (SEQ ID NO: 74), VIP(6-19) (SEQ ID NO: 75), VIP(6-20) (SEQ IDNO: 76), VIP(6-21) (SEQ ID NO: 77), VIP(6-22) (SEQ ID NO: 78), VIP(6-23)(SEQ ID NO: 79), VIP(6-24) (SEQ ID NO: 80), VIP(6-25) (SEQ ID NO: 81),VIP(6-26) (SEQ ID NO: 82), VIP(6-27) (SEQ ID NO: 83), VIP(10-28) (SEQ IDNO: 92), VIP(16-25) (SEQ ID NO: 85), VIP(16-26) (SEQ ID NO: 86),VIP(16-27) (SEQ ID NO: 87), VIP(16-28) (SEQ ID NO: 88).

In another aspect, the invention relates to the use of a VIP in themanufacture of a medicament for the therapeutic or prophylactictreatment of hypertension. Preferably the VIP fragment is one or moreVIP fragments selected from the group consisting of VIP(4-10) (SEQ IDNO: 29), VIP(4-11) (SEQ ID NO: 30), VIP(4-12) (SEQ ID NO: 31), VIP(4-13)(SEQ ID NO: 328), VIP(4-14) (SEQ ID NO: 33), VIP(4-15) (SEQ ID NO: 34),VIP(4-16) (SEQ ID NO: 35), VIP(4-17) (SEQ ID NO: 36), VIP(4-18) (SEQ IDNO: 37), VIP(4-19) (SEQ ID NO: 38), VIP(4-20) (SEQ ID NO: 39), VIP(4-21)(SEQ ID NO: 40), VIP(4-22) (SEQ ID NO: 41), VIP(4-23) (SEQ ID NO: 42),VIP(4-24) (SEQ ID NO: 43), VIP(4-25) (SEQ ID NO: 44), VIP(4-26) (SEQ IDNO: 45), VIP(4-27) (SEQ ID NO: 46), VIP(4-28) (SEQ ID NO: 90), VIP(5-10)(SEQ ID NO: 47), VIP(5-11) (SEQ ID NO: 48), VIP(5-12) (SEQ ID NO: 49),VIP(5-13) (SEQ ID NO: 50), VIP(5-14) (SEQ ID NO: 51), VIP(5-15) (SEQ IDNO: 52), VIP(5-16) (SEQ ID NO: 53), VIP(5-17) (SEQ ID NO: 54), VIP(5-18)(SEQ ID NO: 55), VIP(5-19) (SEQ ID NO: 56), VIP(5-20) (SEQ ID NO: 57),VIP(5-21) (SEQ ID NO: 58), VIP(5-22) (SEQ ID NO: 59), VIP(5-23) (SEQ IDNO: 60), VIP(5-24) (SEQ ID NO: 61), VIP(5-25) (SEQ ID NO: 62), VIP(5-26)(SEQ ID NO: 63), VIP(5-27) (SEQ ID NO: 64), VIP(5-28) (SEQ ID NO: 65),VIP(6-10) (SEQ ID NO: 66), VIP(6-11) (SEQ ID NO: 67), VIP(6-12) (SEQ IDNO: 68), VIP(6-13) (SEQ ID NO: 69), VIP(6-14) (SEQ ID NO: 70), VIP(6-15)(SEQ ID NO: 71), VIP(6-16) (SEQ ID NO: 72), VIP(6-17) (SEQ ID NO: 73),VIP(6-18) (SEQ ID NO: 74), VIP(6-19) (SEQ ID NO: 75), VIP(6-20) (SEQ IDNO: 76), VIP(6-21) (SEQ ID NO: 77), VIP(6-22) (SEQ ID NO: 78), VIP(6-23)(SEQ ID NO: 79), VIP(6-24) (SEQ ID NO: 80), VIP(6-25) (SEQ ID NO: 81),VIP(6-26) (SEQ ID NO: 82), VIP(6-27) (SEQ ID NO: 83), VIP(10-28) (SEQ IDNO: 92), VIP(16-25) (SEQ ID NO: 85), VIP(16-26) (SEQ ID NO: 86),VIP(16-27) (SEQ ID NO: 87), VIP(16-28) (SEQ ID NO: 88).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Comparison of the degree of myocardial fibrosis in WKY rats on ahigh salt diet after 4 week infusion of vehicle, VIP(6-16) (SEQ ID NO:72) or VIP(4-16) (SEQ ID NO: 35).

FIG. 2: Comparison of myocardial fibrosis in rats aged 14 weeks (zerotime) then on a high salt diet for 4 weeks and receiving either vehicleinfusion or VIP(6-16) (SEQ ID NO: 72) infusion (5 pmol/kg/min) for 4weeks).

FIG. 3: Myocardial fibrosis in 18 week old WKY rats after 4 weeks on ahigh salt diet and treated with VIP(6-16) (SEQ ID NO: 72), VIP(10-28)(SEQ ID NO: 92), VIP(16-28) (SEQ ID NO: 88), VIP(4-16) (SEQ ID NO: 35)and VIP(1-12) (SEQ ID NO: 91) or vehicle Control. All peptides wereinfused at a dose of 5 pmol/kg/min for 4 weeks.

FIG. 4: Myocardial fibrosis in 18 week old WKY rats after 4 weeks on ahigh salt diet and treated with native VIP (SEQ ID NO: 1), VIP(6-28)(SEQ ID NO: 84), VIP(6-16) (SEQ ID NO: 72), or vehicle Control. Allpeptides were infused at a dose of 5 pmol/kg/min for 4 weeks.

FIG. 5: Myocardial fibrosis in 18 week old WKY rats after 4 weeks on ahigh salt diet and treated with native VIP (SEQ ID NO: 1), VIP(6-28)(SEQ ID NO: 84), VIP(10-28) (SEQ ID NO: 92), VIP(16-28) (SEQ ID NO: 88),VIP(4-16) (SEQ ID NO: 35) and VIP(1-12) (SEQ ID NO: 92) or vehicleControl. All peptides were infused at a dose of 5 pmol/kg/min for 4weeks.

FIG. 6: Systolic blood pressure (SBP) in SHR after 4 weeks on a highsalt diet and treated with VIP(1-28) (SEQ ID NO: 1), VIP(4-10) (SEQ IDNO: 29), VIP(4-12) (SEQ ID NO: 31), VIP(4-16) (SEQ ID NO: 35), VIP(4-20)(SEQ ID NO: 39), VIP(4-24) (SEQ ID NO: 43) and VIP(4-28) (SEQ ID NO: 90)or control. All peptides were infused at a dose of 5 pmol/kg/min for 4weeks.

FIG. 7: Systolic blood pressure (SBP) in SHR after 4 weeks on a highsalt diet and treated with VIP(1-28) (SEQ ID NO: 1), VIP(6-10) (SEQ IDNO: 66), VIP(6-12) (SEQ ID NO: 682), VIP(6-16) (SEQ ID NO: 72),VIP(6-20) (SEQ ID NO: 76), VIP(6-24) (SEQ ID NO: 80) and VIP(6-28) (SEQID NO: 84) or control. All peptides were infused at a dose of 5pmol/kg/min for 4 weeks.

FIG. 8: Systolic blood pressure (SBP) in SHR after 4 weeks on a highsalt diet and treated with VIP(1-28) (SEQ ID NO: 1), VIP(16-20) (SEQ IDNO: 20), VIP(16-24) (SEQ ID NO: 93) and VIP(16-28) (SEQ ID NO: 88) orcontrol. All peptides were infused at a dose of 5 pmol/kg/min for 4weeks.

FIG. 9: Systolic blood pressure (SBP) in SHR after 4 weeks on a highsalt diet and treated with VIP(1-28) (SEQ ID NO: 1), VIP(1-12) (SEQ IDNO: 91), and VIP(10-28) (SEQ ID NO: 92) or control. All peptides wereinfused at a dose of 5 pmol/kg/min for 4 weeks.

DETAILED DESCRIPTION

It has now been found, quite surprisingly in view of the well acceptedviews held in this field, that VIP fragments lacking amino acids andmotifs thought to be important for their function are neverthelessuseful therapeutic agents to reverse or delay onset of myocardialfibrosis, or prevent onset of fibrosis in subjects at risk of developingmyocardial fibrosis. Thus, VIP fragments are also useful in thetreatment of congestive cardiac failure.

The use of the pharmaceutical compositions of the invention in thetreatment of myocardial fibrosis or associated conditions represents anew class of therapeutic agents for these conditions. Existingtreatments for myocardial fibrosis or associated conditions usuallytarget one, or at the most two, of the known causative mechanisms inmyocardial fibrosis. Without wishing to be bound by any particularmechanism of action, it is believed that the pharmaceutical preparationsof the invention may target virtually all the currently known promotersof myocardial fibrosis.

On the basis of the present studies, and not wishing to be bound bytheory, it is postulated that VIP fragments act as a major regulator toprevent the development of fibrosis and that the depletion of VIP mayunleash the synthesis of a number of profibrotic mediators, therebycausing myocardial injury. The VIP fragments of the present inventionseem to be able to act in much the same way as the native VIP but aremore suited for therapeutic applications due to smaller size and henceincreased stability and ease of manufacture.

Further, and unexpectedly, a number of fragments lacking certain aminoacid residues and domains commonly thought to be important for itsfunction have been shown to be active in the present studies.Particularly useful fragments are VIP(6-16) (SEQ ID NO: 72), VIP(16-28)(SEQ ID NO: 88), VIP(10-28) (SEQ ID NO: 92), VIP(6-12) (SEQ ID NO: 68),VIP(6-10) (SEQ ID NO: 66), VIP(6-20) (SEQ ID NO: 76), VIP(6-24) (SEQ IDNO: 80) and VIP(4-16) (SEQ ID NO: 35). Further, fragments listed inTable 1 are also expected to be useful in the methods of the presentinvention. Fragments VIP(1-12) (SEQ ID NO: 91) and VIP(6-28) (SEQ ID NO:84) have been described earlier and are not included in the presentinvention. It will be understood that the present invention alsoencompasses within its scope certain analogues of the VIP fragmentswhich are based on conservative substitution of one or more amino acidsof the VIP fragments with amino acids which do not alter the biologicalactivities of the VIP fragments. Such substitutions would be well knownto those skilled in the art and would not require more than simpletrial-and-error using well established techniques. Hence, the term “VIPfragment” as used in the context of the present invention is intended toencompass such analogues.

Other useful VIP fragments are listed in Table 1. All the sequencesrelate to VIP and fragments of human origin but due to the very highlevel of amino acid conservation, VIP and fragments thereof derived fromother mammalian species are also contemplated and encompassed by thepresent invention.

The present invention also contemplates pharmaceutical compositionswhich include active VIP fragments. Such compositions may include anytype of dosage form such as tablets, capsules, powders, liquidformulations, delayed or sustained release, patches, snuffs, nasalsprays and the like. The formulations may additionally include otheringredients such as dyes, preservatives, buffers and anti-oxidants, forexample. The physical form and content of the pharmaceuticalformulations contemplated are conventional preparations that can beformulated by those skilled in the pharmaceutical formulation field andare based on well established principles and compositions described in,for example, Remington: The Science and Practice of Pharmacy, 19^(th)Edition, 1995; British Pharmacopoeia 2000 and similar formulation textsand manuals. The compositions of the present invention may also includeother active agents useful in the treatment of cardiovascularconditions.

The route and frequency of administration of the compositions of thepresent invention will depend on the treatment requirements and thenature of the molecule to be administered. Thus the formulations may besuitably prepared for administration by intravenous, intramuscular orsubcuticular injection. VIP fragments may also be suitable for mucosaladministration such as oral, sublingual, nasal and the like. Theseparameters are easily established by those skilled in the art.

The pharmaceutical compositions of the invention have been shown to beeffective in preventing or slowing down progression of establishedmyocardial fibrosis, as well as in reducing the degree (reversal) ofestablished fibrosis and thus important in therapeutic applications. Thecompositions of the present invention are also useful for prophylacticor therapeutic treatment of congestive cardiac failure. These areimportant findings with respect to the range and severity of conditionswhich can be treated with the compositions of the present invention.

Further, the compositions of the present invention may be usedprophylactically in subjects at risk of developing myocardial fibrosisor an associated condition. As an example of subjects in the riskcategory are those having hypertension, diabetes, myocarditis, ischaemicheart disease, drugs such as daunorubicin and others which are used incancer chemotherapy, genetic predisposition, other conditions such asConn's Syndrome and Phaeochromocytoma, high salt diet and the like. Theterm “prophylactic” as used in the context of the present invention isintended inter alia to encompass treatments used to prevent or slow downthe development of fibrosis in the at risk group. High proportion ofsubjects which may be given prophylactic treatment may already havesigns of early heart failure on echocardiography.

The term “associated condition” as used in the context of the presentinvention and in reference to myocardial fibrosis is intended toencompass, without limitation, left ventricular hypertrophy, diastolicdysfunction, myocarditis, cardiomyopathy, left ventricular dysfunctionand congestive cardiac failure (for which myocardial fibrosis may be anunderlying pathology). The associated condition may also includeconditions which give rise to generation of profibrotic mediators orconditions which predispose a subject to myocardial fibrosis, such asfor example hypertension and/or high salt intake, diseases such asdiabetes and the like.

By conserving the VIP content of the cardiac muscle in a subject with,or at risk of developing, myocardial fibrosis or associated condition,through the use of the compositions of the present invention significanttherapeutic benefits can be achieved including reduction of fibrosis,reduction in the level, production or activity of pro-fibroticmediators, reduction in progression of fibrosis, reduction in collagenformation or enhancing collagen degradation in the cardiac muscle.

The invention will now be described more particularly with reference tonon-limiting examples.

EXAMPLES

All general methodology and techniques have been described in detail inPCT/AU2005/000835, incorporated in its entirety herein by reference.

Example 1 Effect of VIP Fragment Infusion on Fibrosis in Animal Modelsof Fibrosis

Four animal models of myocardial fibrosis were used (animals obtainedfrom Australian Animal Resources, Perth, Western Australia, Australia)

-   i) WKY rat fed a high salt diet-   ii) WKY rat fed a high salt diet and given L-NAME    (w-monomethyl-nitro-L-arginine, Sigma Chemical Co.) 10 mg/kg/day in    the drinking water-   iii) WKY rats with diabetes induced by streptozotocin injection 60    mg/kg-   iv) SHR rat fed a 2.2% salt diet for 4 weeks

In each model the rats were randomised to VIP(4-16)(Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln) (SEQ ID NO: 35),VIP(6-16) (Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln) (SEQ ID NO: 72),VIP(4-20)(Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-)(SEQ ID NO: 39), or VIP(4-24)(Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn)(SEQ ID NO: 43), VIP(16-28)(Gln-Met-Ala-Val-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn) (SEQ ID NO: 88),VIP(10-28)(Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn)(SEQ ID NO: 92), VIP(6-12) (Phe-Thr-Asp-Asn-Tyr-Thr-Arg) (SEQ ID NO:68), VIP(6-10) (Phe-Thr-Asp-Asn-Tyr) (SEQ ID NO: 66), VIP(6-20)(Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-) (SEQ IDNO: 76), or VIP(6-24)(Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn)(SEQ ID NO: 80) (All obtained from or synthesised by Auspep, Australia)or vehicle control (Hartman's Solution, Baxter) infusion for 4 weeks viaAlzet minipump (n=6-8 each experimental group). The dose of each peptidewas 5 pmol/kg/min.

In models i) and ii) 14 week old WKY rats were commenced on high saltdiet or high salt diet plus L-NAME. They underwent operative insertionof an Alzet minipump for infusion of VIP or vehicle. After 4 weeks therats were anaesthetised and the hearts harvested. Myocardial fibrosislevels were quantitated.

In model iii) rats are injected with streptozotocin 60 mg/kg at 14 weeksof age. After 8 weeks the diabetic rats are randomised to peptideinfusion (5 pmol/kg/min) or no treatment. The peptides are administeredas above. After a further 4 weeks the rats are anaesthetised and thehearts harvested as above.

In model iv) 14 week old SHR rats are commenced on a 2.2% salt diet.They undergo operative insertion of an Alzet minipump for peptide orvehicle infusion. After 4 weeks the rats are anaesthetised and thehearts harvested. Myocardial fibrosis levels are quantitated as above.

The degree of myocardial fibrosis is quantitated by two methods in knownmanner (refer Ye V Z C, Hodge G, Yong J L C & Duggan K A (2002) Earlymyocardial fibrosis is associated with depletion of vasoactiveintestinal peptide in the heart Exp. Physiol 87:539-546 Ye V Z C, HodgeG, Yong J L C & Duggan K A (2003) Myocardial VIP and myocardial fibrosisinduced by nitric oxide synthase inhibition in the rat Acta Physiol.Scand. 179:353-360. Ye V Z C, Hodge G, Yong J L C & Duggan K A (2004)Vasopeptidase inhibition reverses myocardial VIP depletion and decreasesmyocardial fibrosis in salt sensitive hypertension Europ. J. Pharmacol.485:235-242).

A significant improvement was found in the hearts of the treated rats inthat the myocardial fibrosis index was significantly lower in thetreated rats compared to the control groups (FIG. 1).

Example 2 Effect of VIP Fragment Treatment on Regression of Fibrosis inAnimal Models of Fibrosis

To determine whether VIP(6-16) (SEQ ID NO: 72), VIP(6-20) (SEQ ID NO:76) and VIP(6-24) (SEQ ID NO: 80) infusion caused regression of existingfibrosis as well as prevented progression of fibrosis two groups ofstudies were performed. The degree of myocardial fibrosis in untreated14 week old WKY rats was compared with the degree of fibrosis in 18 weekold WKY rats after 4 weeks treatment with a high salt diet or a highsalt diet plus L-NAME (10 mg/kg/day) and either VIP(6-16) (SEQ ID NO:72), VIP(6-20) (SEQ ID NO: 76) and VIP(6-24) (SEQ ID NO: 80) (5pmol/kg/min) or vehicle control infusion (see FIG. 2)

Preliminary results are shown in FIG. 2. The data clearly showregression of myocardial fibrosis following VIP(6-16) (SEQ ID NO: 72)infusion. The regression of fibrosis may be due to either reduction incollagen formation or enhancement of its degradation. Although notwishing to be bound by any particular mechanism of action, theregression of myocardial fibrosis is likely to be due to the action ofcollagenases, which play a part in collagen resorption.

The importance of the present invention to health care will beimmediately apparent to one skilled in the art upon reading thisdisclosure. Although the capacity to treat cardiac failure has improvedsignificantly with the advent of angiotensin converting enzyme (ACE)inhibitors and angiotensin receptor blockers, as well as the realisationthat aldosterone antagonists and beta blockers improve outcome in laterstage disease, the addition of the pharmaceutical preparations of theinvention, which act to prevent the progression of the underlying lesion(fibrosis), or even reverse fibrosis, has the capacity to prevent theescalation of mild to severe disease and hence to substantially reducethe health care burden. The overall size of certain VIP fragments andtheir activity makes them ideally suitable as targets for drugdevelopment.

Example 3 Effect of VIP Fragment Treatment on Blood Pressure in AnimalModels of Hypertension

To determine whether VIP and fragments were effective in controllingblood pressure, Spontaneous Hypertensive Rats (SHR) were acclimated toblood pressure measurement by tail cuff plethysmography and then theywere placed on a 2.2% salt diet for 4 weeks.

The rats were randomized to Control (Hartman's Solution) vehicleinfusion, VIP(1-28)(His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn)(SEQ ID NO: 1), VIP(4-10) (Ala-Val-Phe-Thr-Asp-Asn-Tyr) (SEQ ID NO: 29),VIP(4-12) (Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg) (SEQ ID NO: 31),VIP(4-16) (Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln) (SEQ IDNO: 35), VIP(4-20)(Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys)(SEQ ID NO: 39), VIP(4-24)(Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn)(SEQ ID NO: 43), VIP(4-28)(Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn)(SEQ ID NO: 90), VIP(6-10) (Phe-Thr-Asp-Asn-Tyr) (SEQ ID NO: 66),VIP(6-12) (Phe-Thr-Asp-Asn-Tyr-Thr-Arg) (SEQ ID NO: 68), VIP(6-16)(Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln) (SEQ ID NO: 72), VIP(6-20)(Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys) (SEQ IDNO: 76), VIP(6-24)(Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn)(SEQ ID NO: 80), VIP(6-28)(Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn)(SEQ ID NO: 84), VIP(16-20) (Gln-Met-Ala-Val-Lys) (SEQ ID NO: 20),VIP(16-24) (Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn) (SEQ ID NO: 93),VIP(16-28) (Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn) (SEQ IDNO: 88), VIP(1-12) (His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg)(SEQ ID NO: 91) and VIP(10-28)(Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn)(SEQ ID NO: 92), VIP(4-10) (Ala-Val-Phe-Thr-Asp-Asn-Tyr) (SEQ ID NO:29).

Each peptide was infused at 5 pmol/kg/min.

Blood pressure was measured by tail cuff plethysmography twice weeklyfor 4 weeks.

The resultant systolic blood pressure (SBP) measurements are shown inFIGS. 6-9. Several of the fragments showed a reduction in SPB relativeto the control solution. VIP itself was not seen to have any significanteffect in reducing SBP, but a number of fragments, notably VIP(6-28)(SEQ ID NO: 84), VIP(4-24) (SEQ ID NO: 43), VIP(4-28) (SEQ ID NO: 90),and more particularly VIP(4-16) (SEQ ID NO: 35), VIP(4-12) (SEQ ID NO:31), VIP(4-20) (SEQ ID NO: 39), VIP(6-20) (SEQ ID NO: 76) and VIP(6-24)(SEQ ID NO: 80) achieved significant reductions in SBP. FIG. 6illustrates to some extent the difficulty in predicting VIP fragmentactivity from structure. VIP(4-16) (SEQ ID NO: 35) is less efficaciousthan either VIP(4-12) (SEQ ID NO: 31), which has 4AA less, or VIP(4-20)(SEQ ID NO: 39), which is 4AA longer.

VIP(6-28) (SEQ ID NO: 84) was disclosed in PCT/AU2005/000835 as beingeffective for preventing myocardial fibrosis.

It is to be appreciated that other embodiments and variants of thecompositions, methods and uses of the invention, in keeping with theteaching and the spirit of the invention described, are contemplated andthat these are within the scope of the invention.

TABLE 1 VIP fragments and amino acid sequences (native VIP included for reference)Amino acid position No.  and SEQ ID NO 1 2 3 4 5 6 7 8 9 10 11 12 13 1415 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 VIP (SEQ ID NO: 1)His Ser Asp Ala Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gln Met AlaVal Lys Lys Tyr Leu Asn Ser Ile Leu Asn VIP 11-17 (SEQ ID NO: 2) Thr ArgLeu Arg Lys Gln Met VIP 13-20 (SEQ ID NO: 3) Leu Arg Lys Gln Met Ala ValLys VIP 7-27 (SEQ ID NO: 4) Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gln MetAla Val Lys Lys Tyr Leu Asn Ser Ile Leu Asn VIP 1-27 (SEQ ID NO: 5) HisSer Asp Ala Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gln Met Ala ValLys Lys Tyr Leu Asn Ser Ile Leu VIP 1-26 (SEQ ID NO: 6) His Ser Asp AlaVal Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gln Met Ala Val Lys Lys TyrLeu Asn Ser Ile VIP 1-23 (SEQ ID NO: 7) His Ser Asp Ala Val Phe Thr AspAsn Tyr Thr Arg Leu Arg Lys Gln Met Ala Val Lys Lys Tyr LeuVIP 1-22 (SEQ ID NO: 8) His Ser Asp Ala Val Phe Thr Asp Asn Tyr Thr ArgLeu Arg Lys Gln Met Ala Val Lys Lys Tyr VIP 1-21 (SEQ ID NO: 9) His SerAsp Ala Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gln Met Ala Val LysLys VIP 1-18 (SEQ ID NO: 10) His Ser Asp Ala Val Phe Thr Asp Asn Tyr ThrArg Leu Arg Lys Gln Met Ala VIP 1-14 (SEQ ID NO: 11) His Ser Asp Ala ValPhe Thr Asp Asn Tyr Thr Arg Leu Arg VIP 1-11 (SEQ ID NO: 12) His Ser AspAla Val Phe Thr Asp Asn Tyr Thr VIP 1-10 (SEQ ID NO: 13) His Ser Asp AlaVal Phe Thr Asp Asn Tyr VIP 1-6 (SEQ ID NO: 14) His Ser Asp Ala Val PheVIP 9-18 (SEQ ID NO: 15) Asn Tyr Thr Arg Leu Arg Lys Gln Met AlaVIP 15-28 (SEQ ID NO: 16) Lys Gln Met Ala Val Lys Lys Tyr Leu AsnVIP 11-28 (SEQ ID NO: 17) Thr Arg Leu Arg Lys Gln Met Ala Val Lys LysTyr Leu Asn VIP 4-28 (SEQ ID NO: 18) Ala Val Phe Thr Asp Asn Tyr Thr ArgLeu Arg Lys Gln Met Ala Val Lys Lys Tyr Leu Asn VIP 2-28 (SEQ ID NO: 19)Ser Asp Ala Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gln Met Ala ValLys Lys Tyr Leu Asn VIP 16-20 (SEQ ID NO: 20) Gln Met Ala Val LysVIP 16-19 (SEQ ID NO: 21) Gln Met Ala Val VIP 17-25 (SEQ ID NO: 22) MetAla Val Lys Lys Tyr Leu Asn Ser VIP 14-22 (SEQ ID NO: 23) Arg Lys GlnMet Ala Val Lys Lys Tyr VIP 15-28 (SEQ ID NO: 89) Lys Gln Met Ala ValLys Lys Tyr Leu Asn Ile Leu Asn VIP 15-21 (SEQ ID NO: 24) Lys Gln MetAla Val Lys Lys VIP 18-28 (SEQ ID NO: 25) Ala Val Lys Lys Tyr Leu AsnIle Leu Asn VIP 19-28 (SEQ ID NO: 26) Val Lys Lys Tyr Leu Asn Ile LeuAsn VIP 21-28 (SEQ ID NO: 27) Lys Tyr Leu Asn Ile Leu AsnVIP 22-28 (SEQ ID NO: 28) Tyr Leu Asn Ile Leu AsnVIP 4-10 (SEQ ID NO: 29) Ala Val Phe Thr Asp Asn TyrVIP 4-11 (SEQ ID NO: 30) Ala Val Phe Thr Asp Asn Tyr ThrVIP 4-12 (SEQ ID NO: 31) Ala Val Phe Thr Asp Asn Tyr Thr ArgVIP 4-13 (SEQ ID NO: 32) Ala Val Phe Thr Asp Asn Tyr Thr Arg LeuVIP 4-14 (SEQ ID NO: 33) Ala Val Phe Thr Asp Asn Tyr Thr Arg Leu ArgVIP 4-15 (SEQ ID NO: 34) Ala Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg LysVIP 4-16 (SEQ ID NO: 35) Ala Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg LysGln VIP 4-17 (SEQ ID NO: 36) Ala Val Phe Thr Asp Asn Tyr Thr Arg Leu ArgLys Gln Met VIP 4-18 (SEQ ID NO: 37) Ala Val Phe Thr Asp Asn Tyr Thr ArgLeu Arg Lys Gln Met Ala VIP 4-19 (SEQ ID NO: 38) Ala Val Phe Thr Asp AsnTyr Thr Arg Leu Arg Lys Gln Met Ala Val VIP 4-20 (SEQ ID NO: 39) Ala ValPhe Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gln Met Ala Val LysVIP 4-21 (SEQ ID NO: 40) Ala Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg LysGln Met Ala Val Lys Lys VIP 4-22 (SEQ ID NO: 41) Ala Val Phe Thr Asp AsnTyr Thr Arg Leu Arg Lys Gln Met Ala Val Lys Lys TyrVIP 4-23 (SEQ ID NO: 42) Ala Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg LysGln Met Ala Val Lys Lys Tyr Leu VIP 4-24 (SEQ ID NO: 43) Ala Val Phe ThrAsp Asn Tyr Thr Arg Leu Arg Lys Gln Met Ala Val Lys Lys Tyr Leu AsnVIP 4-25 (SEQ ID NO: 44) Ala Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg LysGln Met Ala Val Lys Lys Tyr Leu Asn Ser VIP 4-26 (SEQ ID NO: 45) Ala ValPhe Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gln Met Ala Val Lys Lys Tyr LeuAsn Ser Ile VIP 4-27 (SEQ ID NO: 46) Ala Val Phe Thr Asp Asn Tyr Thr ArgLeu Arg Lys Gln Met Ala Val Lys Lys Tyr Leu Asn Ser Ile LeuVIP 4-28 (SEQ ID NO: 90) Ala Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg LysGln Met Ala Val Lys Lys Tyr Leu Asn Ser Ile Leu AsnVIP 5-10 (SEQ ID NO: 47) Val Phe Thr Asp Asn TyrVIP 5-11 (SEQ ID NO: 48) Val Phe Thr Asp Asn Tyr ThrVIP 5-12 (SEQ ID NO: 49) Val Phe Thr Asp Asn Tyr Thr ArgVIP 5-13 (SEQ ID NO: 50) Val Phe Thr Asp Asn Tyr Thr Arg LeuVIP 5-14 (SEQ ID NO: 51) Val Phe Thr Asp Asn Tyr Thr Arg Leu ArgVIP 5-15 (SEQ ID NO: 52) Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg LysVIP 5-16 (SEQ ID NO: 53) Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys GlnVIP 5-17 (SEQ ID NO: 54) Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys GlnMet VIP 5-18 (SEQ ID NO: 55) Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg LysGln Met Ala VIP 5-19 (SEQ ID NO: 56) Val Phe Thr Asp Asn Tyr Thr Arg LeuArg Lys Gln Met Ala Val VIP 5-20 (SEQ ID NO: 57) Val Phe Thr Asp Asn TyrThr Arg Leu Arg Lys Gln Met Ala Val Lys VIP 5-21 (SEQ ID NO: 58) Val PheThr Asp Asn Tyr Thr Arg Leu Arg Lys Gln Met Ala Val Lys LysVIP 5-22 (SEQ ID NO: 59) Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys GlnMet Ala Val Lys Lys Tyr VIP 5-23 (SEQ ID NO: 60) Val Phe Thr Asp Asn TyrThr Arg Leu Arg Lys Gln Met Ala Val Lys Lys Tyr LeuVIP 5-24 (SEQ ID NO: 61) Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys GlnMet Ala Val Lys Lys Tyr Leu Asn VIP 5-25 (SEQ ID NO: 62) Val Phe Thr AspAsn Tyr Thr Arg Leu Arg Lys Gln Met Ala Val Lys Lys Tyr Leu Asn SerVIP 5-26 (SEQ ID NO: 63) Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys GlnMet Ala Val Lys Lys Tyr Leu Asn Ser Ile VIP 5-27 (SEQ ID NO: 64) Val PheThr Asp Asn Tyr Thr Arg Leu Arg Lys Gln Met Ala Val Lys Lys Tyr Leu AsnSer Ile Leu VIP 5-28 (SEQ ID NO: 65) Val Phe Thr Asp Asn Tyr Thr Arg LeuArg Lys Gln Met Ala Val Lys Lys Tyr Leu Asn Ser Ile Leu AsnVIP 6-10 (SEQ ID NO: 66) Phe Thr Asp Asn Tyr VIP 6-11 (SEQ ID NO: 67)Phe Thr Asp Asn Tyr Thr VIP 6-12 (SEQ ID NO: 68) Phe Thr Asp Asn Tyr ThrArg VIP 6-13 (SEQ ID NO: 69) Phe Thr Asp Asn Tyr Thr Arg LeuVIP 6-14 (SEQ ID NO: 70) Phe Thr Asp Asn Tyr Thr Arg Leu ArgVIP 6-15 (SEQ ID NO: 71) Phe Thr Asp Asn Tyr Thr Arg Leu Arg LysVIP 6-16 (SEQ ID NO: 72) Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys GlnVIP 6-17 (SEQ ID NO: 73) Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gln MetVIP 6-18 (SEQ ID NO: 74) Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gln MetAla VIP 6-19 (SEQ ID NO: 75) Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys GlnMet Ala Val VIP 6-20 (SEQ ID NO: 76) Phe Thr Asp Asn Tyr Thr Arg Leu ArgLys Gln Met Ala Val Lys VIP 6-21 (SEQ ID NO: 77) Phe Thr Asp Asn Tyr ThrArg Leu Arg Lys Gln Met Ala Val Lys Lys VIP 6-22 (SEQ ID NO: 78) Phe ThrAsp Asn Tyr Thr Arg Leu Arg Lys Gln Met Ala Val Lys Lys TyrVIP 6-23 (SEQ ID NO: 79) Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gln MetAla Val Lys Lys Tyr Leu VIP 6-24 (SEQ ID NO: 80) Phe Thr Asp Asn Tyr ThrArg Leu Arg Lys Gln Met Ala Val Lys Lys Tyr Leu AsnVIP 6-25 (SEQ ID NO: 81) Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gln MetAla Val Lys Lys Tyr Leu Asn Ser VIP 6-26 (SEQ ID NO: 82) Phe Thr Asp AsnTyr Thr Arg Leu Arg Lys Gln Met Ala Val Lys Lys Tyr Leu Asn Ser IleVIP 6-27 (SEQ ID NO: 83) Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gln MetAla Val Lys Lys Tyr Leu Asn Ser Ile Leu VIP 6-28 (SEQ ID NO: 84) Phe ThrAsp Asn Tyr Thr Arg Leu Arg Lys Gln Met Ala Val Lys Lys Tyr Leu Asn SerIle Leu Asn VIP 16-25 (SEQ ID NO: 85) Gln Met Ala Val Lys Lys Tyr LeuAsn Ser VIP 16-26 (SEQ ID NO: 86) Gln Met Ala Val Lys Lys Tyr Leu AsnSer Ile VIP 16-27 (SEQ ID NO: 87) Gln Met Ala Val Lys Lys Tyr Leu AsnSer Ile Leu VIP 16-28 (SEQ ID NO: 88) Gln Met Ala Val Lys Lys Tyr LeuAsn Ser Ile Leu Asn

The invention claimed is:
 1. A method of therapeutic treatment of myocardial fibrosis, wherein the method comprises administering to a subject in need thereof a composition comprising one or more VIP fragments selected from the group consisting of: VIP(10-28) (SEQ ID NO: 92), VIP(16-28) (SEQ ID NO: 88), and conservative substitutions thereof that do not alter the biological activity of the fragment.
 2. The method of claim 1, wherein the method slows the progression of myocardial fibrosis.
 3. The method of claim 1, wherein the method reduces the degree of myocardial fibrosis.
 4. The method of claim 1, wherein the method treats myocardial fibrosis by inhibiting or reducing the production of fibrotic mediators, reducing collagen formation, enhancing collagen degradation, or lowering blood pressure.
 5. A method of therapeutic treatment of myocardial fibrosis by reducing hypertension, wherein the method comprises administering to a subject in need thereof a composition comprising one or more VIP fragments selected from the group consisting of: VIP(10-28) (SEQ ID NO: 92), VIP(16-28) (SEQ ID NO: 88), and conservative substitutions thereof that do not alter the biological activity of the fragment.
 6. The method of claim 5, wherein the method slows the progression of myocardial fibrosis.
 7. The method of claim 5, wherein the method reduces the degree of myocardial fibrosis. 